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Roles for the VCP co-factors Npl4 and Ufd1 in neuronal function in Drosophila melanogaster

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Journal of Genetics and Genomics 2017年第10期44卷 493-501页

作者： Dwayne J.Byrne mark J.Harmon Jeremy C.Simpson Craig Blackstone Niamh C. o'Sullivan UCD School of Biomolecular and Biomedical Science UCD Conway Institute University College Dublin Dublin 4 Ireland UCD School of Biology and Environmental Science UCD Conway Institute of Biomolecular and Biomedical Research University College Dublin Dublin 4Ireland Cell Biology Section Neurogenetics Branch National Institute of Neurological Disorders and Stroke National Institutes of Health Bethesda MD 20892 USA

The VCP-Ufd1-Npl4 complex regulates proteasomal processing within cells by delivering ubiquitinated proteins to the proteasome for *** in VCP are associated with two neurodegenerative diseases,amyotrophic lateral sclerosis（ALS） and inclusion body myopathy with Paget＇s disease of the bone and frontotemporal dementia（IBMPFD）,and extensive study has revealed crucial functions of VCP within *** contrast,little is known about the functions of Npl4 or Ufd1 in *** neuronalspecific knockdown of Npl4 or Ufd1 in Drosophila melanogaster,we infer that Npl4 contributes to microtubule organization within developing motor ***,Npl4 RNAi flies present with neurodegenerative phenotypes including progressive locomotor deficits,reduced lifespan and increased accumulation of TAR DNA-binding protein-43 homolog（TBPH）.Knockdown,but not overexpression,of TBPH also exacerbates Npl4 RNAi-associated adult-onset neurodegenerative *** contrast,we find that neuronal knockdown of Ufd1 has little effect on neuromuscular junction（NMJ） organization,TBPH accumulation or adult *** findings suggest the differing neuronal functions of Npl4 and Ufd1 in vivo.

关键词： Proteasome TDP-43 accumulation Neurodegeneration Drosophila

Preventing roof fall fatalities during pillar recovery:A ground control success story

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International Journal of Mining Science and Technology 2017年第1期27卷 107-113页

作者： mark Christopher Gauna Michael MSHA Pittsburgh Safety and Health Technology CenterPittsburghPA 15236USA

For decades, pillar recovery accounted for a quarter of all roof fall fatalities in underground coal *** showed that a miner on a pillar recovery section was at least three times more likely to be killed by a roof fall than other coal miners. Since 2007, however, there has been just one fatal roof fall on a pillar line. This paper describes the process that resulted in this historic achievement. It covers both the key research findings and the ways in which those insights, beginning in the early 2000 s, were implemented in mining practice. one key finding was that safe pillar recovery requires both global and local *** stability is addressed primarily through proper pillar design, and became a major focus after the2007 Crandall Canyon mine disaster. But the most significant improvements resulted from detailed studies that showed that local stability, defined as roof control in the immediate work area, could be achieved with three interventions:(1) leaving an engineered final stump, rather than extracting the entire pillar,(2) enhancing roof bolt support, particularly in intersections, and(3) increasing the use of mobile roof supports(MRS). A final component was an emphasis on better management of pillar recovery *** included a focus on worker positioning, as well as on the pillar and lift sequences, MRS operations,and hazard identification. As retreat mines have incorporated these elements into their roof control plans,it has become clear that pillar recovery is not ‘‘inherently unsafe." The paper concludes with a discussion of the challenges that remain, including the problems of rib falls and coal bursts.

关键词： Retreat mining Roof support Room-and-pillar Ground control

Unanticipated multiple seam stresses from pillar systems behaving as pseudo gob–case histories

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International Journal of Mining Science and Technology 2017年第1期27卷 131-137页

作者： Gauna Michael mark Christopher Pittsburgh Safety and Health Technology Center Mine Safety and Health Administration(MSHA)PittsburghPA 15236USA

Underground coal mining in the U.S. is conducted in numerous regions where previous workings exist above and/or below an actively mined seam. Miners know that overlying or underlying fully extracted coal areas, also known as gob regions, can result in abutment stresses that affect the active mining. If there was no full extraction, and the past mining consists entirely of intact pillars, the stresses on the active seam are usually minimal. However, experience has shown that in some situations there has been sufficient yielding in overlying or underlying pillar systems to cause stress transfer to the adjoining larger pillars or barriers, which in turn, transfer significant stresses onto the workings of the active seam. In other words, the overlying or underlying pillar system behaves as a ‘‘pseudo gob." The presence of a pseudo gob is often unexpected, and the consequences can be severe. This paper presents several case histories, summarized briefly below, that illustrate pseudo gob phenomenon:(1) pillar rib degradation at a West Virginia mine at 335 m depth that contributed to a rib roll fatality,(2) pillar rib deterioration at a Western Kentucky mine at 175 m depth that required pillar size adjustment and installation of supplemental bolting,(3) roof deterioration at an eastern Kentucky mine at 400 m depth that stopped mine advance and required redirecting the section development,(4) coal burst on development at an eastern Kentucky mine at 520 m depth that had no nearby pillar recovery, and(5) coal burst on development at a West Virginia mine at the relatively shallow depth of 335 m that also had no nearby pillar recovery. The paper provides guidance so that when an operation encounters a potential pseudo gob stress interaction the hazard can be mitigated based on an understanding of the mechanism encountered.

关键词： Underground mining Coal Multiple seam Gob Ground control

Differentially expressed genes in hepatocellular carcinoma induced by woodchuck hepatitis B virus in mice

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World Journal of Gastroenterology 2001年第4期7卷 575-578页

作者： mark Feitelson Department of Pathology Second Military Medical UniversityShanghai 200433China

INTRoDUCTIoNHepatocellular carcinoma(HCC)is one of the major causes of death in the *** mechanism of carcinogenesis is unknown,although it is widely accepted that HBV and HCV are clsely related to liver cancer[1-5[1-5].Previously,a variety of studies have described the differences in gene expression which distinguished tumor from nontumor[6-11].Cloning of the genes,especially the genes associated with HBV and HCV,is still very important to account for the development of liver cancer.

关键词： Animals Carcinoma, Hepatocellular Cloning, Molecular DNA, Complementary Databases, Nucleic Acid Gene Expression Regulation, Neoplastic Gene Expression Regulation, Viral Hepatitis B Hepatitis B Virus, Woodchuck Humans Mice Polymerase Chain Reaction Research Support, Non-U.S. Gov't

Heart healthy=prostate healthy： SELECT, the symbolic end of preventing prostate cancer via heart unhealthy and over anti-oxidation mechanisms？

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Asian Journal of Andrology 2012年第2期14卷 243-244页

作者： mark A Moyad Department of Urology University of Michigan Medical Center Ann Arbor MI 48109-0330 USA

The Selenium and Vitamin E Cancer Prevention Trial （SELECT） randomized over 35 000 men into four groups： high-dose vitamin E （400 IU day-1）, high-dose selenium （200 mcg day-1）, combination of vitamin E and sele... 详细信息

关键词： prostate cancer Heart healthy prostate healthy anti-oxidation

Preventing aggressive prostate cancer with proven ：ardiovascular disease preventive methods

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Asian Journal of Andrology 2015年第6期17卷 874-877页

作者： mark A Moyad Department of Urology University of MichiganMedical Center 1500 East Medical Center DriveAnn Arbor MI 48109 USA

Cardiovascular disease （CVD） has been the number one cause of death in the U.S. for 114 of the last 115 years. Risk factors for prostate cancer have primarily mirrored risk proven risk factors for CVD, especially aggressive disease. obesity, dyslipidemia, glucose intolerance, metabolic syndrome, unhealthy dietary habits or caloric excess, lack of physical activity, and inflammation are just some of these shared risk factors. The evidence also suggests proven CVD preventive measures are identical to prostate cancer preventive measures, especially in regard to aggressive disease. Thus, apart from lifestyle measures that can encourage optimal heart and prostate health there are potentially several dietary supplements that need to be avoided in healthy men because they may also increase the risk of prostate cancer. However, there are also several low-cost, generic, safe in the appropriate individuals, and naturally derived agents that could reduce prostate cancer risk, and these can be discussed and remembered utilizing the acronym S.A.M. （statins, aspirin, and/or metformin）.

关键词： Preventing aggressive methods

The ＇omics revolution and our understanding of sperm cell biology

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Asian Journal of Andrology 2011年第1期13卷 6-10页

作者： mark A Baker School of Environmental and Life Sciences University of Newcastle Research Fellow Priority Research Centre in Reproductive Science University of Newcastle Callaghan NSW 2308 Australia

The foundations of proteomics are to study gene products and their regulatory roles within cells. Paradoxically, the only evidence that sperm cells make new proteins is through mitochondrial protein synthesis. Yet despite this, spermatozoa are the perfect candidates for mass spectrometry and hence, proteomic analysis. These enterprising cells use a plethora of post-translational modifications in order to gain functionality following their production within the testis. By using a combination of two-dimensional polyacrylamide gel electrophoresis （2D-PAGE）, and more recently liquid chromatography-mass spectrometry （LC-MS）/MS, recent advances in sperm cell biology, through the use of proteomics, is making unparalleled progress. The protein inventory lists being generated have shed light on transmembrane proteins, kinases and chaperones never previously recognized. In addition, the ability to isolate either phosphopeptides or glycopeptides and quantify the differences between cells of two different populations make proteomic analysis of spermatozoa a real chance to finally answer some age old questions.

关键词： capacitation DIGE epididymis LC-MS proteomics quantitation sperm maturation spermatozoa

Design Improvements and Validation of a Novel Fully 3D Printed Analogue Lumbar Spine Motion Segment

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Journal of Bionic Engineering 2024年第3期21卷 1388-1396页

作者： Siril Teja Dukkipati mark Driscoll Musculoskeletal Biomechanics Research Lab Department of Mechanical EngineeringMcGill University845 Sherbrooke St.W(163)MontréalQCH3A 0C3Canada orthopaedic Research Lab Montreal General Hospital1650 Cedar Ave(LS1.409)MontréalQCH3G 1A4Canada

Spine biomechanical testing methods in the past few decades have not evolved beyond employing either cadaveric studies or finite element modeling ***,both these approaches may have inherent cost and time *** studies are the present gold standard for spinal implant design and regulatory approval,but they introduce significant variability in measurements across patients,often requiring large sample *** element modeling demands considerable expertise and can be computationally expensive when complex geometry and material nonlinearity are *** analogue spine models could complement these traditional methods as a low-cost and high-fidelity alternative.A fully 3D printable L-S1 analogue spine model with ligaments is developed and validated in this *** stiffness of the model under pure bending loading in flexion-extension,Lateral Bending(LB)and Axial Rotation(AR)is evaluated and compared against historical ex vivo and in silico ***,the effect of interspinous,intertransverse ligaments and the Thoracolumbar Fascia(TLF)on spinal stiffness is evaluated by systematic construction of the *** flexion,model Range of Motion(RoM)was 12.92±0.11°(ex vivo:16.58°,in silico:12.96°)at *** LB,average RoM was 13.67±0.12°at 7.5 Nm(ex vivo:15.21±1.89°,in silico:15.49±0.23°).Similarly,in AR,average RoM was 17.69±2.12°at 7.5Nm(ex vivo:14.12±0.31°,in silico:15.91±0.28°).The addition of interspinous and intertransverse ligaments increased both flexion and LB stiffnesses by approximately 5%.Addition of TLF showed increase in flexion and AR stiffnesses by 29%and 24%,*** novel model can reproduce physiological RoMs with high repeatability and could be a useful open-source tool in spine biomechanics.

关键词： Lumbar spine 3D printing Intervertebral disc Biomechanical testing Spine mechanics

Androgen synthesis inhibitors in the treatment of castration-resistant prostate cancer

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Asian Journal of Andrology 2014年第3期16卷 387-400页

作者： mark N Stein Rutgers Cancer Institute of New Jersey Department of Surgery Rutgers Robert Wood Johnson Medical SchoolNew Brunswick New Jersey USA. Department of Medicine Department of Surgery Rutgers Robert Wood Johnson Medical SchoolNew Brunswick New Jersey USA. Section of Urologic oncology Department of Surgery Rutgers Robert Wood Johnson Medical SchoolNew Brunswick New Jersey USA.

Suppression of gonadal testosterone synthesis represents the standard first line therapy for treatment of metastatic prostate cancer. However, in the majority of patients who develop castration-resistant prostate cancer （CRPC）, it is possible to detect persistent activation of the androgen receptor （AR） through androgens produced in the adrenal gland or within the tumor itself. Abiraterone acetate was developed as an irreversible inhibitor of the dual functional cytochrome P450 enzyme CYP17 with activity as a 17（^-hydroxylase and 17,20-1yase. CYP17 is necessary for production of nongonadal androgens from cholesterol. Regulatory approval of abiraterone in 2011, based on a phase III trial showing a significant improvement in overall survival （oS） with abiraterone and prednisone versus prednisone, represented proof of principle that targeting AR is essential for improving outcomes in men with CRPC. Inhibition of 17α-hydroxylase by abiraterone results in accumulation of upstream mineralocorticoids due to loss of cortisol-mediated suppression of pituitary adrenocorticotropic hormone （ACTH）, providing a rationale for development of CYP17 inhibitors with increased specificity for 17,20-1yase （orteronel, galeterone and VT-464） that can potentially be administered without exogenous corticosteroids. In this article, we review the development of abiraterone and other CYP17 inhibitors; recent studies with abiraterone that inform our understanding of clinical parameters such as drug effects on quality-of-life, potential early predictors of response, and optimal sequencing of abiraterone with respect to other agents; and results of translational studies providing insights into resistance mechanisms to CYP17 inhibitors leading to clinical trials with drug combinations designed to prolong abiraterone benefit or restore abiraterone activity.

关键词： androgen synthesis castration-resistant prostate cancer treatment